Abstract

Protein homeostasis is maintained through a balance among protein synthesis, folding, assembly and degradation. The latter
is crucial also to prevent accumulation of misfolded products in the cell. The conjugation to ubiquitin marks proteins for
degradation by the proteasome. Secretory and membrane proteins are monitored for proper folding and oligomerisation in the
endoplasmic reticulum (ER). In this compartment, defective proteins are recognised and targeted to the proteasome in a process
called ER‐associated protein degradation or ERAD. A first step of retrotranslocation across the ER membrane to the cytosol
is required. Ubiquitylation is carried out by ER enzymes and is also functionally intertwined with retrotranslocation. Malfunctioning
of ERAD machinery or accumulation of folding‐defective proteins in the ER is associated with various human diseases ranging
from neurodegenerative disorders to cancer. The design of drugs that meliorate ERAD or promote protein folding could provide
new therapeutic strategies against these diseases.

Key Concepts

The ER is the organelle where secretory or membrane proteins are folded and assembled with the aid of chaperones and oxidoreductases
before they exit the ER.

A quality control inside the ER monitors protein folding, and terminally misfolded or unassembled proteins are selectively
recognised and targeted to ERAD.

Trimmed N‐glycans of terminally misfolded luminal glycoproteins are signals for recognition as a substrate for degradation.

ERAD substrates are sorted to different degradation pathways based on the location of the misfolded region and the topology
of the protein.

ERAD involves several factors that are organised in modules and cooperate in the processes of substrate recognition, retrotranslocation,
ubiquitylation and targeting of substrates to the proteasome where cleavage occurs.

The retrotranslocation of the substrates from the ER to the cytosol is mediated by still undefined channel proteins.

Retrotranslocated substrates are ubiquitylated on the cytosolic side of the ER by membrane‐associated E3 ubiquitin ligases.

In ERAD, ubiquitylation is dynamically interconnected with substrate extraction from the ER membrane, delivery to the proteasome,
removal of the N‐glycan chains from glycosylated polypeptides and processing of the substrates for final disposal.

Malfunctioning of ERAD components or accumulation of misfolded substrates causes various human diseases.